Mutation rate is a fundamental determinant of the speed of genomic evolution that increases the background frequency of non-selected mutations genome-wide as well as infrequent mutations in genes that are selected for progression to cancer. Esophageal adenocarcinoma (EA) is known to have high levels of background mutations, but how this mutation frequency changes over time before EA is unknown. Barrett's esophagus (BE) is the only known precursor to EA, and although BE is commonly called premalignant, current clinical practices selectively identify slowly or nonprogressive BE that remains stable for a lifetime (overdiagnosis), and miss rapidly progressive BE that then presents as an advanced EA with high mortality (underdiagnosis). During the current funding period, we made transformative advances in a case-cohort study indicating that chromosome instability underiies rapid progression with a four year window of opportunity for eariy detection. Using one of the best characterized BE cohort:s available, we propose to build on these advances in a case-control study to investigate the full spectrum of somatic genomic alterations (SGA) over time in a population with BE who progressed to EA and in a population with indolent BE that did not progress to EA. We hypothesize the frequency of different classes of mutations changes over time and that these genome dynamics can be used to extend the window of opportunity for eariy detection of EA. We will perform whole genome sequencing of BE biopsies to determine the frequency of somatic micromutations (intergenic, intronic, and exomic point mutations, small indels and complex mutations), structural variations, breakpoints and chromosomal alterations in spatially mapped biopsies collected over time prior to and at the time of EA diagnosis in cases, and during endoscopic follow-up in BE controls who did not progress, matched on level of arraySGA (copy gains, copy losses, copy neutral LOH, and homozygous deletions) and follow-up time in a case-control study. We hypothesize that the variation in frequency over time of different classes of somatic mutations is significantly different in progressors and the frequency of mutations within each mutation class is more spatially heterogeneous as a function of time in progressors, compared to nonprogressors. Our research seeks to shift the existing clinical practice of treating all conditions based on a static pathologic description at a single point in time to the study of genome dynamics of non- or slowly progressive and rapidly progressive disease to increase the window of eariy detection of cancer. Barrett's esophagus is the only known precursor to esophageal adenocarcinoma, a rapidly increasing, highly lethal cancer, but most people with Barrett's esophagus remain free from this cancer for a lifetime. Current clinical practices selectively detect indolent Barrett's esophagus and miss 95% of patients who rapidly progress to cancer. Our study identifies changes in mutation frequency overtime and space that can be used to extend windows of opportunity for eariy detection or prevention of esophageal adenocarcinoma.